1. Field of the Invention
The present invention pertains to osmotically controlled implantable delivery devices, and more particularly to a delivery device having a two-way miniature valve and a dynamically self-adjusting flow channel for the regulation of back-diffusion and fluid delivery rate in an osmotically driven delivery system.
2. Description of the Related Art
Controlled delivery of beneficial agents, such as drugs, in the medical and the veterinary fields has been accomplished by a variety of methods, including implantable delivery devices, such as implantable osmotic delivery devices. Osmotic delivery systems are very reliable in delivering a beneficial agent over an extended period of time, called an administration period. In general, osmotic delivery systems operate by imbibing fluid from an outside environment and releasing controlled amounts of beneficial agent from the delivery system.
Representative examples of various types of delivery devices are disclosed in U.S. Pat. Nos. 3,987,790; 4,865,845; 5,059,423; 5,112,614; 5,137,727; 5,213,809; 5,234,692; 5,234,693; 5,308,348; 5,413,572; 5,540,665; 5,728,396; 5,985,305; and 5,221,278, all of which are incorporated herein by reference. All of the above patents generally include some type of capsule having walls, or portions of walls (for example, semi-permeable membranes) that selectively pass water into the interior of the capsule. The absorption of water by a water-attracting agent contained within the capsule creates an osmotic pressure within the capsule, which then causes a beneficial agent within the capsule to be expelled. Alternatively, the water-attracting agent may be the beneficial agent being delivered to the patient. However, in most cases, a separate agent is used specifically for its ability to draw water into the capsule.
When a separate osmotic agent is used, the osmotic agent may be separated from the beneficial agent within the capsule by a movable dividing member such as a piston. The structure of the capsule is generally rigid such that as the osmotic agent takes in water and expands, the capsule itself does not expand. As the osmotic agent expands, the agent causes the movable dividing member to move, discharging the beneficial agent through an orifice or exit passage of the capsule. The beneficial agent is discharged through the exit passage at the same volumetric rate that water combines with the osmotic agent through the semi-permeable walls of the capsule.
In some known implantable delivery devices, the orifice or exit passage of the capsule is permanently open and thus allows for unimpeded discharge of the beneficial agent. This results in a direct fluid communication between the beneficial agent and water in the surrounding tissue of the patient. Thus, back-diffusion of the water into the beneficial agent reservoir may result. One way in which back-diffusion of water has been reduced is by providing a long orifice or exit passage that can be a variety of shapes, such as straight or spiral.
In other known implantable delivery devices, the orifice or exit passage of the capsule is covered with a stretchable or elastic member or band, to reduce back-diffusion of water into the beneficial agent reservoir. The stretchable or elastic band allows discharge of the beneficial agent once a threshold pressure has been overcome. The stretchable or elastic member or band closes the orifice when the pressure in the device is less than the threshold pressure. However, in these types of devices there is little or no control of the pressure that can build up as the device adjusts to changes in temperature and/or internal or external pressure.
In still other known implantable delivery devices, the orifice or exit passage is at least partially made of a stretchable or elastic material that acts to reduce back-diffusion of water into the beneficial agent reservoir. This stretchable or elastic material deforms once a threshold pressure has been achieved in the device to allow discharge of the beneficial agent. The stretchable orifice material closes when the internal pressure in the device is less than the threshold pressure. However, in these types of devices there is little or no control of the pressure that can build up as the device adjusts to changes in temperature and/or internal or external pressure.
In general, osmotic delivery systems rely on the flow of interstitial body fluid across a rate-limiting membrane (also known as a semi-permeable membrane) to drive the osmotic agent expansion that in turn drives the delivery or discharge of the beneficial agent. During the period immediately following implantation, this interstitial fluid may also diffuse into the beneficial agent via a beneficial agent delivery channel (also known as an orifice or exit passage). Such diffusion is undesirable because it results in an uncontrolled dilution of the beneficial agent formulation.
In those prior known designs which attempt to limit or prevent back-diffusion without covering the orifice or exit passage, one limitation has been that a relatively long diffusion path is required to prevent or impede back-diffusion of the fluid into the beneficial agent compartment. The long orifice, diffusion path, or exit channel in these known designs has been formed by molding intricate detail into plastic or by machining high tolerance surfaces into metal. These approaches are costly to manufacture and occupy a relatively large volume, causing the implant to have an increased size.
A further drawback of known implantable delivery devices is that these devices do not compensate for variations in temperature and internal pressure that can cause the implantable delivery device to deliver beneficial agent temporarily at high or low rates. Typically, an implantable, osmotically driven delivery system will have been stored at ambient room temperature (approximately 20 to 22° C.) prior to implantation into a patient. Within a few hours following implantation, the system will subsequently come to thermal equilibrium with the patient (approximately 37° C.). This increase in temperature may cause the beneficial agent formulation within the implantable device to expand, which may result in a pressurization of the system and a rapid, short-duration delivery of beneficial agent often referred to as a start-up “burst.” This burst is typically followed by a short period of somewhat low agent delivery (typically lasting from less than one day to 5 days) during which time the osmotic pressure is increased to a degree equal to that of the piston friction. As the internal pressure of the implantable device increases, the rate of beneficial agent delivery will rise until it obtains a steady state. Since it is the purpose of an osmotic delivery system to deliver a defined concentration of beneficial agent at a fixed rate, both the start-up “burst” and the subsequent “lag” in delivery are undesirable.
A further aspect of an implantable, osmotically driven beneficial agent delivery system is that it is subject to external pressure or temperature changes (e.g., scuba diving, a hot bath, or temperature cycling during shipping) which may, in turn, result in transient spikes in the beneficial agent delivery profile.
It is possible with the current designs to develop high enough pressures within the implantable osmotic delivery device that one or more of the implant components fails or is expelled. In an effort to reduce the possibility of component failure or expulsion, previous designs have provided grooves in the reservoir walls and/or ribs in the semi-permeable membrane or holes in the wall of the device which are open if a component of the device moves out of position. These approaches add cost to the device by requiring additional machining to the part designs.
Accordingly, it is an objective of the present invention to minimize the start-up “burst” by containing the beneficial agent with a spring-loaded valve until the internal, osmotic-induced pressure is great enough to overcome the applied spring force, thereby opening the valve and allowing controlled release of the agent. It is also an objective of this invention that the post-start-up “lag” in beneficial agent delivery be minimized or eliminated as a further result of the elimination of the initial agent “burst.” A further consequence of this minimization of start-up “burst” and post start-up “lag” is that the system may achieve the desired steady-state performance significantly sooner than in known implantable agent delivery devices.
Another objective of the present invention is to provide for the elimination of back-diffusion in a relatively inexpensive manner and without requiring a relatively large or long orifice, diffusion path, or exit channel.
An additional objective of the present invention is to provide an implantable osmotic delivery device capable of containing the total osmotic pressure that can develop within the device without requiring relatively expensive and sophisticated fluid flow bypass pathways.